Dr George Kinghorn’s talk, 2002: “An Update on Herpes Simplex”

Dr Kinghorn is the consultant in genitourinary medicine at the Royal Hallamshire Hospital, Sheffield. He is very interested in the herpes simplex virus and is a member of the Herpes Simplex Virus Advisory Panel, which is a sub-group of the prestigious British Association for Sexual Health and HIV. He is also a member of the Independent Advisory Group for Sexual Health and HIV/AIDS which advises the government on sexual health services. Over the years, we have sent him some ‘difficult cases’ which he has been able to sort out with ease!

He gave the ‘annual talk’ to members of the Herpes Viruses Association in 2002. Afterwards, he answered our questions – read on

The epidemiology of herpes simplex [how common the virus is] and its pattern of transmission is very different in other parts of the world.

For example:
– Infection rates in the US are much higher. (It might be because of this that their internet sites are very alarmist.)
– Many studies are carried out in Seattle. What happens in Seattle is not necessarily the same as herpes simplex epidemiology here,” warns Dr Kinghorn. He continued:

Epidemiology – how common is genital herpes?

New patients with herpes simplex seen in GUM clinics in the UK have gone up from 13,274 in 1991 to 17,853 in 2001*. It is seen more commonly in women than in men and this is probably because, as in various infections, transmission is easier from man to woman than from woman to man. In years gone by when I was first working in GU medicine, we only used to talk about herpes simplex type 2. There was a clear differentiation between ‘type 1 above the neck’ and ‘type 2 below the waist’. But it isn’t like that any more: the proportion of new cases we see of type 1, especially in women, exceeds those with type 2. This is a trend that is seen everywhere, but of all the countries that report the number of cases, the UK probably has the highest proportion of genital infection with type 1. It is interesting why this should be. It is actually because of improved socio-economic conditions and standards of hygiene, so there is a lower level of infection with type 1 in childhood.

* Editor: This is not the total number. Woolley & Chandiok 1996, found that on average a GP sees 2.4 people each year, about two thirds new cases: 50,000 people. Also 10.5% of our female members and 4.5% of our male members diagnosed themselves or were diagnosed by a friend so the total can be increased by a further 8%, giving 74,000 new cases yearly.

It used to be the case that the majority of people became infected with herpes simplex type 1 before they became adolescents. And that certainly affected the proportion of individuals who developed symptoms when they acquired herpes simplex type 2. We now have very much reduced infection in childhood. If you look at the graph: in 1986 by age 14 one third were infected, by 1995 it was lower than one quarter.

This means that when we become sexually active, the majority of us have no acquired immunity to herpes simplex at all. So that if you are exposed to herpes simplex type 1 you may acquire that genitally or facially and have unpleasant symptoms – or similarly with herpes simple type 2.

People worry a great deal about transmitting genital infection but they are less concerned about oral herpes [cold sores] and yet the main way women get genital infection is from cold sores via oral sex. One is considered to be nuisance but the other is associated with a degree of stigma. And I think that is unhelpful.

A new report, about to be published, shows that in a variety of countries, Morocco, Sri Lanka, India, Estonia and Brazil, half of 5 or 6 year olds are herpes simplex type 1 positive and by adolescence the infection rate has risen to 75%. This is quite different from what now happens in the UK. It takes to the age 30 for half of to be HSV type 1 positive and to age 50 for 75% of us to be HSV-1 positive. The majority of us get infected with herpes simplex type 1 after we become sexually active rather than before as in developing countries. And if you acquire type 1 after the age of adolescence, then you are almost as likely to get it genitally as orally. So this is the reason why we see so much genital type 1 these days.

Type 1 infection may prevent type 2 symptoms

It has been said that if you have infection with type 1, you have some immunity against infection with herpes simplex type 2. Probably what happens is that if you have type 1, when you acquire type 2 you are less likely to have symptoms of it. So having cold sores means you are less likely to have symptomatic illness when you come across herpes simplex type 2. It may be mild or without symptoms at all. It is when you have never had cold sores that you get major symptoms.

Type 2 is more common in developing countries than we have here but they have fewer people with symptoms because of previous infection with type 1. Do we encourage grandma with cold sores to kiss our children? I don’t know the answer to that – but it is certainly the case with all herpes viruses that if you acquire them as an adult you are more likely to get a severe illness. We know this with chickenpox: adults are more likely to have complications such as pneumonia whereas a child may just have a few spots and few days off school.

In the US there was concern because serological studies [blood tests] showed that between the 80s and 90s type 2 infection increased by over 30%. They now find that almost a quarter of their population has type 2. This graph shows that here the level of infection is much lower.

HSV-2 seroprevalence rates in UK

Males

Females

STD clinic

Cowan et al, 1994

17%

25%

Antenatal clinic

Ades et al, 1990

–

10%

Blood donors

Cowan et al, 1994

3%

12%

General population

Brown et al, 1997

3.2%

7.8%

In the UK probably 7-8% overall of the population has been infected with herpes simplex type 2. There are some factors that affect the positivity rate. So the rate of infection will depend on what group you test. The rate always goes up with age, it is higher in women than men, it is always higher in black populations than white (for increased genetic susceptibility as is true of many forms of infection), it is higher in men who have sex with men than heterosexuals. So you can get a figure in one country that varies according to the group that you study – you can get an answer which fits what your particular belief is.

The overall infection rate with herpes simplex type 2 in this country is significantly lower than in the US. We find that rates of infection are higher in all developing countries, 20% or more, so when I visit the States, I tell them they are a developing country!

Prevalence differs around the world. Some countries choose not to record their genital herpes infection rate – I think that is not a good idea. It is better to know so that you can plan the services accordingly. And although I am showing infection rates for populations, I do think it is more important to look at individuals.

The difference between types 1 and 2

Anthony: Could you explain the herpes simplex type 1 and type 2 figures? What are the effects of getting one or the other of them? Is one more virulent that the other?

GK: The majority of people, these days, catch herpes simplex type 1 as adults, because as mentioned before, fewer of us are getting it as kids. When you get herpes simplex type 1 as an adult, I think you are equally as likely to have symptomatic recurrences whichever type you catch – but no good study has been done, so this is my educated guess.

As to virulence: it depends where you’ve got it. These viruses have evolved beautifully. Herpes simplex type 1 is much more virulent if you get it round the mouth, you are more likely to get symptomatic recurrence, and if you get herpes simplex type 2 around the mouth you rarely if ever get symptomatic recurrences there. So the virulence depends on where you catch it. It will also depend on a variety of individual susceptibility factors, our genetic make-up certainly has a effect. I rather suspect it is an individual thing, we inherit from our parents genes which will usually determine whether we get symptomatic recurrences or not. It is the same with thrush, there is a genetic susceptibility to getting it: we see mums and sisters who get it. It is not because you get more virulent strains of candida/ thrush, or herpes simplex, but because of our reaction to it.

Having herpes simplex is normal

It is no different to other herpes viruses: all of us have at least three of them. Most of us have had chickenpox, most of us have had herpes simplex 1 or 2 or both. At least 25% have cytomegalovirus [HHV-5]. When we look at antibodies for Epstein Barr virus [HHV-4] which is the cause of glandular fever, nearly all of us are positive for this even if you have not had symptomatic disease, well over 90% of the adult population is infected. And most of us get humanherpes virus (HHV) 6 and 7 by the age of two.

So what I am suggesting to you is that to be infected with a herpes virus is a state of normality, not an abnormality. We tend to make this into a big deal instead of to say that to be infected with herpes virus is something that happens to all adults, some with symptoms and some of us without.

After first infection with any of the herpes viruses, when they often cause acute manifestations, latent infection develops: in the nerve ganglia for herpes simplex and chickenpox and in the lymphoid tissue or in the tonsils for Epstein Barr. And it is typical of all herpes viruses that they can be reactivated from time to time. Most of us will be shedding Epstein Barr virus from our throat intermittently – you can’t do anything about that, it just happens. Chickenpox often recurs as shingles when you get older. It is because, either through physical or emotional factors, a change takes place in your immune system: the balance between the defence mechanisms that keeps the virus in check is altered and allows symptoms to recur. The key thing therefore is not whether you are infected but whether it is causing symptoms or not – and if it is then what should be done about it.

Herpes simplex and childbirth

Neonatal herpes is an incredibly uncommon condition in this country: 1 in 60,000 which works out at about 10 a year. That’s an incredibly low figure when you consider how many women are infected with herpes simplex. Whereas in the US it is 1 in 2,000 or 3,000 deliveries so it is ten times more common. We now realise that it is not women who have been infected before pregnancy who have the problem. In fact to prevent neonatal herpes it is better to have acquired herpes simplex before you become pregnant because the risk of transmission in those circumstances is very low.

Neonatal herpes occurs when Mum acquires the virus in the 12 weeks before delivery, it is new infections that are the problem. So most doctors do not worry if Mum has herpes simplex, although that is not the perception, people think there will be worries if a mother has herpes simplex. What happens is that women develop antibodies, which cross the placenta, so if the baby were to catch it from the mother, it would be mild and localised disease rather than serious disease which could be life-threatening or cause damage to the nervous system. So having had the virus before pregnancy is a distinct advantage.

Sean: I’ve read about herpes in fish.

GK: Every animal species had its own herpes viruses. People are not able to catch these herpes viruses off animals [except monkey virus ‘simian B’ through a bite].

Natural history of the infection – symptoms

I have indicated that a good proportion of people who are infected have no symptoms, it is a minority who develop symptoms. Blood tests can show that people in the street are carrying the virus although they are not aware of it. Perhaps they got cold sores from their mum as a kid.

By and large, the more severe your primary infection the more likely it is that you will get recurrences, at least in the first year. The number of recurrences tends to decrease over time. We also know that a type 1 genital infection is likely to result in fewer recurrences than type 2 in that area, or than if you have type 1 around the mouth.

Three quarters of the people with the virus are not aware they are carrying it.

The next table shows how many of the people infected with herpes simplex have symptoms.

How many of the people infected with herpes simplex have symptoms

People who have been diagnosed

25%

People who can be taught to recognise their mild symptoms

50%

People who have no symptoms at all

25%

Probably about 1 in 4, or slightly less than that, of the people who have been infected, have been diagnosed. Three quarters of the people with herpes simplex are unaware of it. Studies in Seattle suggest that if the people who carry the virus, but are unaware of it, are educated in what the symptoms of herpes simplex recurrences can be like, then more than half of them can learn to recognise when they get mild symptoms. So overall it would appear that of people who have been infected, about half of them are totally unaware of the situation but may have mild symptoms from time to time. This American study suggests that overall about one quarter of people infected have no symptoms at all.

We do not know if it is the same in the UK as we haven’t done the study. However, I see many people who do know that they are getting symptoms, but they do not call it herpes simplex, and have not been diagnosed. They call it thrush, or a cut, or even cystitis symptoms which they may have had diagnosed and treated, but the cause may be herpes simplex. This can be in women or men. It is interesting to learn what a wide range of symptoms it can cause. As well as having it genitally, the lesions can be on the buttocks, on the thigh, in or around the anus – then people will call it a pile or a fissure. There are a lot of misdiagnoses. If they are getting a sciatic pain down they leg, they think they have sciatica. They may say ‘I get an agonising pain down to my calf and incidentally I get a little sore afterwards.’

How to deal with pain

Neuralgic pain is often dealt with by simple analgesics – aspirin, paracetamol, ibuprofen. But my feeling is that if somebody is getting neuralgic pain that is disabling, they should be given daily suppressive therapy. In fact this can be used as a diagnostic test. People may have weird and wonderful symptoms. If these end when suppressive treatment is given, then you can tell that it is viral. We must remember that people with herpes simplex can get ‘slipped discs’ as well [which are nothing to do with herpes simplex but which cause similar pains]. They are both quite common. So a trial of aciclovir therapy will help decide what is causing the pain.

The severity of the infection varies from individual to individual. The size of the sores is no indication of the illness: insignificant lesions to look at can be quite disabling, large sores may not be particularly painful. Some people have distressing prodromal symptoms – they feel ill or they have uncomfortable neuralgic symptoms before – the sore is not the issue. The fact is we are all different and everybody has to be assessed on their own individual basis.

Asymptomatic shedding

Asymptomatic shedding is the thing that everyone worries about: “What is the likelihood that I am going to transmit this to my nearest and dearest – if he or she has not already been infected?”

We used to say that if you avoid sex when you have a lesion the chance of transmission is low. Studies, again these were done in Seattle, reported that most people who develop an infection catch it off a partner who may have had symptoms in the past but who does not have symptoms at the time. So transmission appears to occur when there are no signs or symptoms there. Studies looking for viral shedding either by viral culture (swabs) or PCR (where you actually amplify the molecules of the specimen and this is more sensitive) can find virus on the skin when they have no signs or symptoms. These studies were done on women who, to my mind amazingly, are prepared to be swabbed twice a day for months on end. Periods of asymptomatic shedding tend to be most marked in the first year after acquiring the infection and then seem to diminish. They are more common just before and just after an outbreak. In some people it is unpredictable. What they have found is most inconvenient: they have found that people will shed virus from time to time from the site of genital infection – just as they will shed from apparently intact skin of the face if they get cold sores. Just as we shed Epstein Barr virus from our throats without having any signs or symptoms.

Transmission

This means that some people will inadvertently transmit the infection to others. It is not entirely predictable. So how easy is it to transmit it to a partner? If we look at couples where one has it and the other does not, you get the impression that everyone should be infected. The figure for infection I use for when they are not using barrier method of contraception in relationships where one partner has it and the other doesn’t is surprisingly low: it is about 10% or less per year. If the ‘uninfected’ partner has herpes simplex type 1 then if they do acquire the infection, they are far less likely to have severe symptomatic disease. The new microbicidal liquids undergoing research are nicknamed ‘liquid condoms’ as they can be used both as contraceptives and to prevent the transmission of STIs and HIV.

What can you do to help to reduce transmission? A study recently shows that using condoms will reduce transmission from men to women. Thought, as yet there are no figures that show that condoms reduce transmission from women to men.

I would like to say that two or three years after you have been infected with herpes simplex this is the risk of infecting a partner. I can’t. There have been no studies. What we can say is that the risk of transmission, like the risk of viral shedding and the risk of having symptomatic recurrence is going to diminish. Does it become absent in some people? I am sure it does, because they have recurrences which bother them for a couple of years and then they stop having recurrences. And some people will have never had any symptoms and yet they can shed virus some time. But we certainly see that in general as recurrences diminish, so too does asymptomatic viral shedding – but it is not a guarantee.

Marian (staff member): I read that in a similar study of transmission to a sexual partner, of the people who caught it, 40% were totally unaware that they had caught it and were surprised with the results of the blood test. And that was in a study about ‘infecting partners’ so they would be aware. So if you went out and madly infected ten people – probably five or even six would be totally unaware?

LAUGHTER

GK: It is true. Probably, the majority of people who are infected are unaware of having been infected. Not that we are advocating that [kind of behaviour] of course!

Protecting others…

Marian: I want to emphasise that, because people are always saying to me on the phone ‘I couldn’t possibly risk giving someone what I’ve got’ but the point is they wouldn’t.

GK: None of us wishes to knowingly cause hurt to others, especially those who are dear to us. However, the world appears to perceive genital herpes as being different to facial cold sores, which are far more common. It is likely that because of their location that cold sores are more easily transmissible than genital herpes, including by asymptomatic transmission from invisible lesions. Yet, most affected people do not avoid kissing others when they do not have any cold sores. I think that it is rather like driving a car. No matter how safely we drive, occasionally there may be an accident. However, what we should expect is that everyone drives as safely as possible, with consideration for other road users, and to ensure that the brakes are kept in good working order!

Marian: And all of us taking a vow of celibacy wouldn’t actually protect everybody else?

GK: No, I do not advocate celibacy, which for most people, is not compatible with a happy, fulfilled existence. To continue the road analogy, we all need to cross the road, but should take as much care to be safe as is reasonably possible when we do so.

Lee: When people have type 2, can they get type 1?

GK: Yes they may. But there is evidence that having herpes simplex type 2 protects you from catching type 1.

Lee: What is the risk you can transmit to each other a different strain of virus [of the same type]?

GK: It has certainly been seen, but by and large, it does not result in symptomatic disease. Could you acquire from your partner a second more virulent strain that caused you to have a different pattern of attacks than before? In effect, I rarely see that. Studies where people have been infected with two different viral types show that it usually doesn’t lead to a difference in the pattern of their episodes. When you have both been infected, whether you get recurrences or not depends on internal factors rather than external ones. People worry hugely “Are we going to pass this virus backwards and forwards?” I don’t think you catch the same virus again, you may catch the other type, but I don’t think that causes any symptoms in the vast majority of people.

Genetics?

Liz: Are there genetic differences to how you respond to different treatments? I can’t find anything to help stop my recurrences.

GK: The norm is that we all get infected and the virus lives in the nerve cell. What is the difference between somebody where it ‘sits there and does nothing’ and somebody who gets further lesions? People are looking at what those factors might be. Particularly, they are looking at what happens at the end of the nerve fibre. Are there special receptors [on the skin cells] which, for genetic reasons, some of us have and some of us don’t have which will make a difference? What happens in the nerve cells is of no consequence at all [the virus remains dormant and causes no symptoms]. What is important is what happens between the nerve fibre and the skin cell.

It may be that for genetic reasons, we have different receptors on the skin cells and these can be targeted [by a drug treatment]. Can we look them to find therapies – these may be topical – or approaches that ameliorate the effect you might have? Can we understand better what is the pathenogenesis – why you have more severe symptoms than somebody else has? It is a case of translating whether this is related to enzymes that might occur in that area or the receptors on cells, so that some people have cells that are much more likely to become infected. There is a variety of different factors that need to be looked at. It is like the analogy I gave you before about thrush. There are women who have a specific problem with recurrent thrush. They are otherwise healthy, they don’t have an immune deficiency that is going to damage their health, they just don’t handle that specific organism well. So I think some people who get severe problems with herpes simplex type 2 just don’t happen to handle that virus well – for reasons which are not yet understood. The better we understand that process the more likely we are going to have new therapies. Rather than a blunderbuss approach – drug, topical or nutritional approach – we might be better able to tailor treatment to the individual.

Current treatments

I have participated in many clinical trials of new drugs, vaccines and other treatments for genital herpes because I would like doctors to be better able to alleviate the distressing symptoms that many people have.

Antiviral pills

The standard treatment for first and recurrent episodes is aciclovir 5 times daily for five days. Recent research shows that you can probably treat recurrent episodes with valaciclovir (‘Valtrex’) twice daily for 2 days, or aciclovir 400 mg three times daily for 3 days. Taking medication five times daily is very inconvenient and I prefer the shorter course with less frequent daily dosing.

The key to effective treatment of recurrences is having your medication available for self-initiated therapy. Used early when there are prodromal [warning] symptoms of an attack, antiviral treatment can probably abort up to a quarter of episodes and will shorten the remainder. (It is important to have medication always available, especially when you are away from home or going on holiday because, sod’s law, that is when the trouble occurs.) Short courses of episodic treatment will alleviate the symptoms of recurrences and shorten their duration but do not prevent future recurrences.

If you are suffering frequent recurrences, which are affecting your normal functioning, then I think every effort should be made to prevent future recurrences with suppressive antiviral treatment. Certainly, having episodes every one to two months can be a severe intrusion.

Our normal prescription for suppression is aciclovir 400 mg twice daily. This drug treatment is not satisfactory taken on a once daily basis. Valtrex can be successfully used by some patients when taken once daily, however for many it also appears to be more effective taken twice daily. The vast majority of people will stop having symptoms.

If symptoms are still persisting despite what should be adequate treatment, then there is often an additional or alternative diagnosis. I see many people who believe that they are resistant to suppressive treatment where further investigation reveals recurrent or persistent thrush or a genital skin condition as the true cause of their symptoms.

Antivirals are safe

Sarah: Is it safe?

GK: Aciclovir has been used now for fifteen or twenty years. [This talk was given in 2002.] The evidence is that it is a remarkably safe drug. In the US, people have been on it for many years. We don’t use it that way in this country. We put people on it for six months or a year and then see what the patient looks like after that. But there is no evidence for long-term damage.

Marian: Will you continue treating them at the GUM clinic if their doctor doesn’t want to give suppressive treatment?

GK: I am married to a GP, so I know of the problems that there can be in primary care. However, I do not believe that any doctor has the choice whether to prescribe treatment or not merely on the basis of some moral judgement. I do not see any difference between the need for treatment for recurrent genital herpes than for other chronic conditions. If it is more convenient for a patient to get regular medication from their GP, then this is what I would recommend. If for whatever reason a patient was unable or unwilling to get their prescriptions from their GP, then I would be prepared to continue giving medication within the GUM clinic setting, though most clinics are not funded to provide this.

I feel so strongly that this condition is so ordinary, so commonplace in terms of how many people are affected that for doctors to maintain the stigma is not helping. I think we must change ‘illnesses’ to ‘conditions’ – not even ‘complaint.’ It is a condition that you deal with in the same way you would deal with other things. It shouldn’t be that different.

Sarah: You mentioned Valtrex, is that better than aciclovir?

GK: Valtrex – valaciclovir – is a clever drug in that the active component is still aciclovir but it has an extra molecule that makes it much better absorbed. If you take it twice a day you get higher drug levels for much longer, so you don’t need to take it five times a day. The trouble with oral aciclovir is that it is not very well absorbed and it gets flushed out of your system so you have to take it more often. Valtrex is 2 x day, Famvir is 3 x day and aciclovir is 5 x a day – but by doubling up the dose you can get away with aciclovir twice a day. These are all on prescription. The only thing you can get over the counter is aciclovir cream which is of limited efficacy.

Famvir costs £2.81, Valtrex costs £2.35 but aciclovir tablets only cost 36p each. This is because aciclovir is now ‘off patent’ and is a generic drug (with a lower case ‘a’).

Female: It is true that there is no greater risk of cervical cancer when you have herpes simplex?

GK: It used to be thought that herpes simplex was a factor in the development of genital cancer. There is now no doubt that it is certain types of papilloma virus, rather than herpes simplex virus, that is the problem. We no longer recommend that women with genital herpes need to have an annual smear test ­ the usual three-yearly smear is all that is required. For most women who have had genital warts, the normal three-yearly smear is also recommended.

Vaccines

I don’t see anything on the immediate horizon that will enter the nerve ganglion where herpes viruses lie dormant and remove latent infection. To get rid of the virus from the nerve sheath you would have to kill the nerve cell, that is not a good thing, by and large. LAUGHTER. What we should perhaps focus more upon is to promote a state of persistent latency, without recurrences, in the same way we do naturally with other herpes viruses. For most of our lives, we are not bothered at all by the chickenpox virus that lives with us in harmony. Some people do have a recurrent episode in later life – that is shingles. Although this illness can be unpleasant and debilitating, it generally only occurs once.

Studies with vaccines so far have been rather disappointing. Both the Chiron and the Glaxo sub-unit vaccines have shown to have some slight effect in women but these have either been limited to short-term benefits, needing repeated vaccine injections for sustained responses, or have only found to benefit women who have no evidence of previous infection with both HSV-1 and HSV-2. The DISC vaccine, which is a live vaccine that has been genetically modified so that it is only able to replicate itself once, has also failed to show benefit in terms of preventing future recurrences.

There are some new vaccines, which use different constituents, that may turn out to have benefits in trials which are continuing.

Triggers

Nigel: Some people say that getting sore skin or having sex triggers an outbreak. Does this mean that for some people the virus is hanging about very near the skin?

GK: This a great question. There are two schools of thought. Some people, including me, believe that there are some virus particles that are near the skin surface, probably in the nerve ending. This would help explain the speed with which some individuals experience a recurrence after having sex. Other people believe that the virus only resides within the nerve ganglion, which is further away from the skin. As yet we do not have a scientifically proven answer that provides a clear answer.

We do know that trauma to the skin is a trigger factor for recurrences. With cold sores of the face, ultraviolet light during a skiing or summer holiday may provoke a recurrence. Likewise for genital herpes, the more traumatic intercourse is, the more likely a recurrence will follow. Skin infection or irritation, such as may occur with thrush, eczema, [or horse-riding], may provoke genital recurrences. It is important in treatment that these provoking factors are also treated, in addition to giving treatment to stop the virus from replicating. The healthier genital skin is, the less the likelihood of recurrent outbreaks.

Nigel: We know of a man who got an outbreak a few hours after sex. As it was always on his foreskin, he had a circumcision. It worked, a year later he was still pleased with the outcome.

GK: I also know of a few anecdotal cases of men whose outbreaks always occurred on the foreskin and were abolished after circumcision. However, most will continue to have outbreaks that appear on different areas of genital skin. I do not generally recommend that men with recurrent genital herpes should undergo circumcision. After all, in the US, where most men are circumcised shortly after birth, there is much more genital herpes than occurs in the UK.